Method of treating a bacterial infection comprising administering amoxycillin

ABSTRACT

Bacterial infections may be treated using a high dosage regimen of amoxycillin. Preferably, the dosage is provided by a bilayer tablet.

This application claims the benefit of Provisional Application U.S. Ser.No. 60/129,074, filed Apr. 13, 1999; U.S. Ser. No. 60/150,727, filedAug. 25, 1999; U.S. Ser. No. 60/159,813, filed Oct. 15, 1999 and U.S.Ser. No. 60/159,838, filed Oct. 15, 1999.

FIELD OF THE INVENTION

This invention relates to a novel method of treatment using amoxycillinand for novel formulations, in particular tablet formulations, for usein such methods.

BACKGROUND OF THE INVENTION

Amoxycillin is a well known β-lactam antibiotic which has been availablefor many years. Despite the suspectibility of amoxycillin to inhibitionby β-lactamases produced by resistant organisms, amoxycillin stillenjoys widespread usage as a broad spectrum antibiotic for the treatmentof commonly occurring bacterial infections. In particular, amoxycillinis particularly effective in treating sore throats—acute bacterialtonsillitis and/or pharyngitis where the causative organism is almostexclusively Streptococcus pyogenes.

Amoxycillin is available commercially in a variety of formulations, forinstance as capsules containing either 250 or 500 mg amoxycillin, astablets comprising 500 or 875 mg amoxycillin, as chewable tabletscomprising either 125 or 250 mg amoxycillin and as dry powderformulation, for reconstitution into an oral suspension. Otherformulation types include dispersible tablets providing 500 mgamoxycillin, chewable effervescent tablets, comprising 125, 250 or 500mg amoxycillin and single dose sachets comprising 750 or 3000 mgamoxycillin. The standard adult dosage is 250 mg three times daily(tid), increasing to 500 mg tid for more severe infections. In addition,the 875 mg tablet is intended for dosing twice daily (bid), as analternative to the dosage regimen of 500 mg tid. Recently, a 1000 mgchewing tablet has been advertised as being under development (ACPharma, see SCRIP No 2472 Sep. 15th 1999, page 11). A high dosage of 3g, bid, is recommended in appropriate cases for the treatment of severeor recurrent purulent infection of the respiratory tract. For shortcourse therapy, in simple urinary tract infections, two 3 g doses, at aninterval of 10-12 hours, are given while for a dental abscess, thedosage is two 3 g doses at an interval of 8 h and for gonorrhoea, asingle dose of 3 g. Furthermore, the use of 1 g of amoxycillin, bid, isused as one arm of a combination therapy, for eradication ofHelicobacter pylori in peptic ulcer disease.

In addition, amoxycillin is provided in combination with the β-lactamaseinhibitor potassium clavulanate in various tablet formulations ofamoxycillin and potassium clavulanate comprising various differentweights and ratios of amoxycillin and potassium clavulanate, forinstance, conventional swallow tablets comprising 250/125, 5001125,500/62.5, and 875/125 mg amoxycillin/clavulanic acid (in the form ofpotassium clavulanate). Such tablets comprise amoxycillin and clavulanicacid in the ratio 2:1, 4:1, 8:1 and 7:1, respectively. The 875/125 mgtablet was developed to provide a tablet formulation which could beadministered in a bid (twice daily) dosage regimen It is also marketedfor tid (three times daily) dosing, in Italy and Spain. The 500/62.5 mgtablet was also developed to provide a tablet formulation which could beadministered in a bid dosage regimen, two such tablets being taken every12 h, in preference to a single 1000/125 mg tablet. A 1000/125 mg singledosage is also available, in France, but as a single dosage sachetrather than a tablet. Typically, the approved regimen provides a singledosage of 125 mg of potassium clavulanate.

In addition, WO 97/09042 (SmithKline Beecham) describes tabletformulations comprising amoxycillin and clavulanic acid in a ratio inthe range 12:1 to 20:1, preferably 14:1. Furthermore, it is suggestedthat the preferred dosage of 1750/125 mg may be provided as two tablets,the first comprising 875/125 mg amoxycillin and clavulanic acid and thesecond 875 mg amoxycillin. The 14:1 ratio is said to be useful for theempiric treatment of bacterial infection potentially caused by drugresistant S pneumoniae (DRSP). This patent application also describespaediatric formulations comprising amoxycillin and clavulanate in a 14:1ratio, for administering amoxycillin dosages of 90 mg/kg/day. Datasuggest that such a dosage may provide antibiotic concentrationssufficient to eradicate DRSP with amoxycillin+/−clavulanic acid MICs≦4μg/ml (Bottenfield et al, Pediatr Infect Dis J, 1998, 17, 963-8).

Existing marketed tablet formulations of amoxycillin are conventional inthat they provide immediate release of the active ingredients once thetablet reaches the stomach. There has also been some interest indeveloping formulations in which the release profile is modified, toallow for a longer interval between dosages, for instances, every 12hours (bid, q12 h), rather than every 8 hours (tid, q8 h).

Thus, for instance, WO 94/06416 (Jagotec AG) describes multi-layeredtablets comprising 500 mg of amoxycillin distributed equally between animmediate release and a slow release layer. Furthermore, WO 95/20946(SmithKline Beecham) describes inter alia a layered tablet comprisingabout 500 mg amoxycillin having a first layer which is an immediaterelease layer and a second layer which is a slow release layer, theratio of amoxycillin between the two layers being about 1:2.6, as wellas an intermediate barrier layer. Further bilayered tablets comprisingclavulanic acid and amoxycillin are described in WO 98/05305 (QuadrantHoldings Ltd). In such tablets, a first layer comprises amoxycillin anda second layer comprises clavulanate and the excipient trehalose, tostabilise the clavulanate component.

In addition, WO 95/28148 (SmithKline Beecham) describes inter aliatablet formulations comprising amoxycillin and, optionally, clavulanatehaving a core comprising amoxycillin coated with a release retardingagent and surrounded by an outer casing layer of amoxycillin andpotassium clavulanate. The release retarding agent is an entericcoating, so that there is a immediate release of the contents of theouter core, followed by a second phase from the core which is delayeduntil the core reaches the intestine. Furthermore, WO 96/04908(SmithKline Beecham) describes inter alia tablet formulations comprisingamoxycillin in a matrix, for immediate release, and granules in adelayed release form comprising amoxycillin. Such granules are coatedwith an enteric coating, so release is delayed until the granules reachthe intestine. WO 96/04908 (SmithKline Beecham) describes inter aliadelayed or sustained release formulations of amoxycillin formed fromgranules which have a core comprising amoxycillin and surrounded by alayer comprising amoxycillin.

In addition, WO 94/27557 (SmithKline Beecham) describes controlledrelease formulations of amoxycillin and clavulanic acid prepared using ahydrophobic waxy material which is then subjected to thermal infusion.

Further controlled release formulations comprising amoxycillin have beendescribed by several groups. Thus, Arancibia et al ((Int J of ClinPharm, Ther and Tox, 1987, 25, 97-100) describe the pharmacokineticproperties and bioavailability of a controlled release formulationcomprising 500 mg of amoxycillin. No further details of the formulationare provided. The formulation was however designed to release 21 to 35%during the first 60 minutes, 51 to 66% at 4 hours, 70 to 80% at 6 hours,81 to 90% at 8 hours and more than 94% at 12 hours. They however foundlittle, if any, correlation between the in vitro dissolution rate andthe pharmacokinetic behaviour in the body. Hilton et al (InternationalJournal of Pharmaceutics, 1992, 86, 79-88) described an alternativecontrolled release tablet having a hydrophilic polymer matrix and a gasrelease system, to provide intragastric buoyancy, to enhance gastricretention time. This showed no advantage over a conventional capsuleformulation, with bioavailability being diminished. In contrast, Hiltonet al (Journal of Pharmaceutical Sciences, 1993, 82, 737-743) describeda 750 mg controlled release tablet incorporating the enteric polymerhydroxypropylmethyl cellulose acetate succinate. This however failed toshow any advantage over a conventional capsule. In particular, thebioavailability was reduced to 64.6% compared with the same dosageprovided in a capsule. More recently, Hoffman et al (Journal ofControlled Release, 1998, 54, 29-37 and WO 98/22091) have described atablet comprising 500 mg of amoxycillin in a matrix comprisinghydroxypropyl methyl cellulose, designed to release 50% of its contentsin the first three hours and complete the drug release process overeight hours. The time above MIC was found to be significantly extended,compared to a capsule formulation, but not enough for a 12 h dosinginterval. The discussion is in the context of a theoretical MIC of 0.2μg/ml.

SUMMARY OF THE INVENTION

The present invention relates to a method of treating bacterialinfections in humans which comprises administering thereto atherapeutically effective amount of amoxycillin in the range 1900 to2600 mg, at a dosage regimen/interval of about 12 hours. Suitably, theinfection is caused by the organisms S pneumoniae (including DrugResistant and Penicillin Resistant S pneumoniae), H influenzae Mcatarrhalis and/or S Pyogenes.

The present invention also relates to a modified release pharmaceuticalformulation comprising amoxycillin in which a first part of amoxycillinare formulated with pharmaceutically acceptable excipients which allowfor immediate release of the first part of amoxycillin, to form animmediate release phase, and further comprising a second part ofamoxycillin formulated with pharmaceutically acceptable excipients whichallow for slow release of the second part of amoxycillin, to form a slowrelease phase.

The present invention also relates to an immediate releasepharmaceutical tablet formulation comprising 1000 mg±5% amoxycillin incombination with pharmaceutically acceptable excipients or carriers.

The present invention also relates to an immediate releasepharmaceutical formulation in the form of a single dose sachetcomprising 2000, 2250 or 2500 mg±5% amoxycillin, or the correspondinghalf quantities thereof, in combination with pharmaceutically acceptableexcipients or carriers.

Other suitable modified or immediate release formulations are describedherein in greater detail.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the structure of various types of layered tablets of thepresent invention, in particular the structure of substantiallycylindrical compressed tablets are shown in longitudinal section. In

FIG. 1A, shows a tablet comprising a first layer (1) and a second layer(2), without any barrier layer or coating layer.

FIG. 1B, shows a tablet comprising a first layer (1), a second layer(2), and a barrier layer (3) sandwiched between the first and secondlayers (1) and (2).

FIG. 1C, shows a tablet comprising a first layer (1), a second layer(2), and a barrier layer (3) located on the end face of the second layer(2).

FIG. 1D, shows a tablet comprising a first layer (1), a second layer(2), a barrier layer (3) sandwiched between the first and second layers(1) and (2), and a coating layer (4) which partly covers the tablet. Thedotted line shows the possibility of the coating layer (4A) covering theentire tablet.

FIG. 1E, shows a tablet comprising a first layer (1) a second layer (2),and a third layer (3) intermediate between the first and second layers(1) and (2). All three of these layers (1), (2) and (3) include activematerial content.

FIG. 2 demonstrates the dissolution profile for tablets of Examples 1and 2.

FIG. 3 demonstrate the pharmacokinetic profiles of Study A

FIG. 4 demonstrates the pharmacokinetic profile for amoxycillin plasmaconcentration for Study B (in which A is formulation V, B is formulationVI, D is formulation VIII).

DETAILED DESCRIPTION OF THE INVENTION

Part of the challenge in providing formulations of amoxycillin in whichthe drug release is effectively modified (and a ready explanation forthe lack of success in the studies already referenced) is the relativelynarrow window for absorption of the drug in the small intestine and therelatively short half life of the drug. Furthermore, the rapidelimination of amoxycillin (excretion half-life is 1.3 hours) makes itdifficult to maintain serum levels as clearance from the body is veryrapid.

In existing tablet formulations comprising amoxycillin, amoxycillin ispresent in the form amoxycillin trihydrate, as the use of this formprovides tablets with greater storage stability than those in whichamoxycillin is present as sodium amoxycillin (see GB 2 005 538, BeechamGroup Ltd). Sodium amoxycillin is however used as the amoxycillincomponent in existing formulations of amoxycillin and potassiumclavulanate adapted for IV administration. The form of sodiumamoxycillin used is a spray-dried form. In addition, EP 0 131 147-A1(Beecham Group plc) describes a further form of sodium amoxycillin,so-called “crystalline odium amoxycillin”. A further process forpreparing crystalline salts of amoxycillin, including sodiumamoxycillin, is described in WO 99/62910 (SmithKline Beecham). Sodiumamoxycillin is relatively water soluble in comparison to amoxycillintrihydrate.

Formulations comprising clavulanic acid and a pharmaceuticallyacceptable organic acid or a salt-like derivative thereof, for examplecalcium citrate, have been described in WO 96/07408 (SmithKlineBeecham). In such formulations, it is postulated that the presence ofthe calcium citrate would help suppress the gastro-intestinalintolerance associated with oral dosing of clavulanate-containingproducts.

Furthermore, U.S. Pat. No. 5,051,262 (Elan Corp) describes theincorporation of an organic acid into a modified release formulation, toprovide a microenvironment in which the locally modified pH helps toprotect the active ingredient from degradation.

Of concern is the increasing resistance of pathogenic organisms, such asthose found in respiratory tract infections, to anti-infective agentssuch as amoxycillin, in particular drug resistant S pneumoniae.Increased resistance to penicillin of S pneumoniae (due to modifiedpenicillin binding proteins) is developing around the world and isaffecting clinical outcomes (see for instance Applebaum P C, Ped Inf DisJ, 1996, 15(10), 932-9). These penicillin resistant S pneumoniae (PRSP)have also been termed “DRSP” as they often exhibit decreasedsusceptibility not only to penicillin but also to a wider range ofantimicrobial classes, including macrolides, azalides, beta-lactams,sulfonamides and tetracyclines. Amoxycillin, along with some of thenewer quinolones, has remained among the most active oral drugs againstthe increasingly resistant isolates of S pneumoniae, based on both MIClevels and pharmacokinetic properties of these compounds. Resistancerates (and MICs) have however continued to increase. Penicillinresistance in S. pneumoniae can be assessed according to criteriadeveloped by the National Committee for Clinical Laboratory Standards(NCCLS), as follows: susceptible strains have MICs of ≦0.06 μg/ml,intermediate resistance is defined as an MIC in the range 0.12 to 1.0μg/ml while penicillin resistance is defined as an MIC of ≧2 μg/ml.Furthermore, it is found that some 10% of pneumococci now have anamoxycillin MIC of 2 μg/ml.

There is consequently a need to provide new formulations of amoxycillinthat combine the known safety profile and broad spectrum with improvedactivity against DRSP, including PRSP, with higher MICs in empirictreatment of respiratory infections where S pneumoniae, H influenzae andM catarrhalis are likely pathogens, as well as S pyogenes.

For β-lactams, including amoxycillin, it is recognised that the timeabove minimum inhibitory concentration (T>MIC) is the pharnacodynamicparameter most closely related to efficacy. For a variety of β-lactams,a bacteriological cure rate of 85 to 100% is achieved when serumconcentrations exceed the MIC for more than about 40% of the dosinginterval (Craig and Andes, Ped Inf Dis J, 1996, 15, 255-259). For a 12hour dosing interval, this is about 4.8 hours.

A further parameter which may be of importance is the ratio of themaximum plasma concentration (Cmax) to the MIC value, as this may berelated to the potential to select for resistance. Too low a ratio mayencourage the development of resistant strains. Preferably, the plasmaC_(max) value is well above the MIC value, for instance, at least twotimes, more preferably at least three times, most preferably at leastfour times, the MIC value.

In a clinical study of an Amoxil 875 mg tablet (SmithKline Beecham), themean amoxycillin pharmacokinetic parameters were shown to be:AUC_(0−∞)=35.4±8.1 μg.hr/mL; C_(max)=13.8±4.1 μg.hr/mL (Physician DeskReference, Medical Economics Co, 52 edition, 1998, 2802). The time aboveMIC was about 40% of the 12 hour dosing interval for an MIC of 2 μg/mland about 30% for an MIC of 4 μg/ml (SmithKline Beecham data).

Based on the foregoing considerations, there is a continuing need toprovide new dosage regimens for amoxycillin giving optimisedpharmacokinetic profiles for amoxycillin, so that therapy is maximised,particularly against more resistant bacteria while the (further)development of resistance is minimised. It has now been found that suchcan be achieved using higher dosages of amoxycillin than previouslycontemplated.

Accordingly, in a first aspect, the present invention provides for amethod of treating bacterial infections in humans which comprises orallyadministering thereto a therapeutically effective amount of amoxycillinin the range 1900 to 2600 mg, preferably 1950 to 2550 mg, at intervalsof about 12 h.

Preferably, the dosage regimen provides a mean plasma concentration ofamoxycillin of 4 μg/mL for at least 4.4 h, preferably at least 4.6 h,more preferably at least 4.8 h, most preferably for about 6 h or longer.

More preferably, the dosage regimen provides a mean plasma concentrationof amoxycillin of 8 μg/ml for at least 4.4 h, more preferably at least4.6 h, most preferably at least 4.8 h.

Preferably, the dosage regimen provides a mean maximum plasmaconcentration (C_(max)) of amoxycillin which is at least 8 μg/mL,preferably at least 12 μg/mL, yet more preferably at least 14 μg/mL,most preferably at least 16 μg/mL.

Preferably, the mean plasma concentration of amoxycillin and the meanmaximum plasma concentration of amoxycillin are measured after oraladministration of a formulation comprising amoxycillin at the start of alight meal.

In a further aspect, the present invention provides for a method oftreating bacterial infections in humans which comprises administeringthereto a therapeutically effective amount of amoxycillin in the range1400 to 1900 mg, preferably 1500 to 1900 mg, at intervals of about 12 h,such that the dosage regimen provides a mean plasma concentration ofamoxycillin of 4 μg/mL for at least 4.4 h, preferably at least 4.6 h,more preferably at least 4.8 h, most preferably for about 6 h or longer;more preferably, a mean plasma concentration of amoxycillin of 8 μg/mlfor at least 4.4 h, more preferably at least 4.6 h, most preferably atleast 4.8 h, and a mean maximum plasma concentration (C_(max)) ofamoxycillin which is at least 8 μg/mL, preferably at least 12 μg/mL, yetmore preferably at least 14 μg/mL, most preferably at least 16 μg/mL.

Bacterial infections amenable to the present invention includeinfections caused by the organisms S pneumoniae (including DrugResistant S pneumoniae (DRSP), for instance Penicillin Resistant Spneumoniae (PRSP)), and/or the respiratory pathogens, most notably Hinfluenzae and M catarrhalis, such as respiratory tract infections,including community acquired pneumoniae (CAP), acute exacerbations ofchronic bronchitis (AECB) and acute bacterial sinusitis (ABS), where thehigher break points achievable through the improved pharmacokineticprofile will be especially advantageous compared to existingantibacterial agents. Further bacterial infections amenable to thepresent invention include infections caused by the organismStreptococcus pyogenes, for instance acute bacterial tonsillitis and/orpharyngitis. The duration of therapy will generally between 7 and 14days, typically 7 days for most indications but 10 days for acutebacterial sinusitis.

The term “amoxycillin” as used herein shall mean amoxycillin or analkaline salt thereof, in particular amoxycillin trihydrate and(crystallised) sodium amoxycillin, without distinction and unlessotherwise indicated.

Unless otherwise indicated, weights of amoxycillin refer to theequivalent weight of the corresponding free acid. In addition, it willbe appreciated that in practice, weights of amoxycillin to beincorporated into a formulation will be further adjusted, in accord withconventional practice, to take account of the potency of theamoxycillin.

In a first embodiment, a dosage of amoxycillin of from 1900 to 2600 mgmay be delivered from an immediate release formulation. Accordingly, ina further aspect, the present invention provides for method of treatingbacterial infections in humans which comprises administering thereto atherapeutically effective amount of amoxycillin in the range 1900 to2600, preferably 1950 to 2550 mg, at intervals of about 12 h, whereinthe dosage is delivered from an immediate formulation.

As used herein, the term “immediate release” shall mean the release ofthe majority of the active material content within a relatively shorttime, for example within 1 hour, preferably within 30 minutes, afteroral ingestion. Examples of such immediate release formulations includeconventional swallow tablets, chewable tablets, dispersible tablets,single dose sachets and capsules.

Representative dosages include 2000, 2250 and 2500 mg of amoxycillin. Apreferred dosage is 2000 mg of amoxycillin.

The dosage in an immediate release formulation may be provided as asingle tablet, for instance a dispersible tablet, a chewable tabletwhich may also be, effervescent and/or dispersible, a single dosecapsule or a single dosage sachet, comprising, for instance, 2000, 2250or 2500 mg amoxycillin. Alternatively, the dosage may be made up of anumber of smaller tablets or capsules, for instance, 2, 3 or 4, whichmay be the same or different. Representative such smaller tabletsinclude swallow tablets, dispersible tablets and chewable tablets whichmay also be effervescent and/or dispersible. Thus, for instance, adosage of 2000 mg amoxycillin may be provided by a combination of fourtablets each comprising 500 mg amoxycillin or two tablets eachcomprising 1000 mg amoxycillin. In addition, a dosage of 2250 mgamoxycillin may be provided by a combination of four tablets comprising500 mg amoxycillin and one tablet comprising 250 mg amoxycillin or twotablets comprising 875 mg amoxycillin and one tablet comprising 500 mgamoxycillin. Furthermore, a dosage of 2500 mg amoxycillin may beprovided by a combination of five tablet comprising 500 mg amoxycillin.Tablets comprising 500 and 875 mg amoxycillin are already commerciallyavailable.

It will be appreciated that immediate release tablets, in particularswallow tablets or dispersible tablets, comprising 1000 mg are novel.Accordingly, in a further aspect, the present invention provides for animmediate release pharmaceutical tablet formulation comprising 1000mg±5% amoxycillin, in a nominal ratio of about 16:1, in combination withpharmaceutically acceptable excipients or carriers. Immediate releasetablets comprising 1000 mg can be readily prepared by adaptingcompositions previously described for 875/125 and 1000/125 mg tablets(see for instance, WO 95/28927 and WO 98/35672, SmithKline Beecham).

It will also be appreciated that immediate release single dosage sachetscomprising 2000 mg, 2250 mg or 2500 mg amoxycillin, or the correspondinghalf quantities thereof, are novel. Accordingly, in a further aspect,the present invention provides for an immediate release pharmaceuticalformulation in the form of a single dose sachet comprising 2000, 2250 or2500 mg±5% amoxycillin, or the corresponding half quantities thereof, incombination with pharmaceutically acceptable excipients or carriers.Such sachets can be readily prepared by adapting compositions previouslydescribed for 875/125 and 1000/125 mg sachets of amoxycillin/potassiumclavulanate (see for instance, WO 92/19277 and WO 98/35672, SmithKlineBeecham).

It will be further appreciated that immediate release chewable tabletscomprising 2000, 2250 or 2500/125 mg are novel. Accordingly, in afurther aspect, the present invention provides for an immediate releasepharmaceutical formulation in the form of a chewable tablet which may beeffervescent and/or dispersible comprising 2000, 2250, or 2500 mgamoxycillin, or the corresponding half quantities thereof, incombination with a chewable base and, if effervescent, an effervescentcouple, and other pharmaceutically acceptable excipients or carriers.Such chewable tablets can be readily prepared by adapting compositionspreviously described for chewable tablets comprising amoxycillin (seefor instance, EP-A-0 396 335, Beecham Group and WO 98/35672, SmithKlineBeecham).

In a second embodiment, a dosage of amoxycillin of from 1900 to 2600 mgamoxycillin may be delivered from a modified release formulation.Accordingly, in a further aspect, the present invention provides formethod of treating bacterial infections in humans which comprisesadministering thereto a therapeutically effective amount of amoxycillinin the range 1400 to 2600 mg, preferably 1900 to 2600 mg, morepreferably 1950 to 2550 mg, at intervals of about 12 h, in which thedosage is delivered from a modified release formulation.

As used herein, the term “modified release” shall mean a release of drugsubstance from a pharmaceutical formulation which is at a slower ratethan from an immediate release formulation such as a conventionalswallow tablet or capsule and may include an immediate release portionor phase and a slow release portion or phase. Modified releaseformulations are well known in the art, see for instance Remington: TheScience and Practice of Pharmacy, Nineteenth Edn, 1995, Mack PublishingCo, Pennsylvania, USA.

Preferably, the modified release formulations of the present inventionare formulated such that the release of amoxycillin is effectedpredominantly through the stomach and small intestine, so thatabsorption through the specific amoxycillin absorption site in the smallintestine is maximised. Preferably, the amoxycillin release profile ismade up of a contribution from an immediate release component which isthen complemented and extended by an on-going contribution from a slowrelease component. Such formulations are preferably formulated such thatthe release of amoxycillin occurs predominantly within 3 hours ofingestion of the formulation.

Representative modified release dosages include 1500, 1750 and 2000 mgof amoxycillin. A preferred dosage is 2000 mg of amoxycillin.

The dosage in a modified release formulation may conveniently beprovided as a number of swallow tablets or capsules, for instance two,three or four which may be the same or different. Thus, for instance, adosage of 2000 mg amoxycillin may be provided by two tablets eachcomprising 1000 mg amoxycillin, two tablets each comprising 500 mgamoxycillin and one tablet comprising 1000 mg amoxycillin or fourtablets each comprising 500 mg amoxycillin. In addition, a dosage of1750 mg amoxycillin may be provided by two tablets each comprising 875mg amoxycillin. A preferred tablet comprises 1000 mg amoxycillin.

The dosage in an modified release formulation may be may also providedas a single tablet. Because of the quantities of drug substance beingused, this would preferably be other than a swallow tablet, for instancea dispersible tablet or a chewable tablet which may also be effervescentand/or dispersible or a dispersible tablet. A single unit dosage mayalso be conveniently provided as a single dosage sachet. It will beappreciated that the dosage may also be provided as a number of smallernon-swallow tablets or sachets, for instance 2×1000 or 4×500 mgamoxycillin.

Preferably, in the modified release formulation, the amoxycillin isprovided in both an immediate release and a slow release phase.

Accordingly, in a further aspect, the present invention provides for amodified release pharmaceutical formulation comprising amoxycillin inwhich a first part of amoxycillin is formulated with pharmaceuticallyacceptable excipients which allow for immediate release of the firstpart of amoxycillin, to form an immediate release phase, and furthercomprising a second part of amoxycillin formulated with pharmaceuticallyacceptable excipients which allow for slow release of the second part ofamoxycillin, to form a slow release phase.

As used herein, the term “slow release” shall mean the gradual, butcontinuous or sustained release, over a relatively extended period ofthe active material content (in this case amoxycillin) after oralingestion and which starts when the formulation reaches the stomach andstarts to disintegrate/dissolve. The release will continue over a periodof time and may continue through until and after the formulation reachesthe intestine. This can be contrasted with the term “delayed release” inwhich release of the active does not start immediately the formulationreaches the stomach but is delayed for a period of time, for instanceuntil when the formulation reaches the intestine when the increasing pHis used to trigger release of the active from the formulation.

Preferably, the modified release formulation has an in vitro dissolutionprofile in which 45 to 65%, preferably 45 to 55% of the amoxycillincontent is dissolved within 30 min; further in which 50 to 75%,preferably 55 to 65% of the amoxycillin content is dissolved within 60min; further in which 55 to 85%, preferably 60 to 70% of the amoxycillincontent is dissolved within 120 min; further in which 70 to 95%,preferably 75 to 85% of the amoxycillin content is dissolved within 180min; and further in which 70 to 100%, preferably 75 to 100% of theamoxycillin content is dissolved within 240 min. In comparison, aconventional, immediate release amoxycillin tablet dissolves essentiallycompletely within 30 minutes. The dissolution profile may be measured ina standard dissolution assay, for instance <711> Dissolution Test,Apparatus 2, provided in USP 23, 1995, at 37.0±0.5° C., using deionisedwater (900 mL) and a paddle speed of 75 rpm.

Preferably, the modified release formulation has a biphasic profile invivo with respect to amoxycillin, that is an initial burst from theimmediate release phase to provide an acceptable C_(max) value,supplemented by a further contribution from the slow release phase, toextend the T>MIC parameter to an acceptable value.

Preferably, the modified formulation provides an “Area Under the Curve”(AUC) value which is substantially similar to, for instance at least80%, preferably at least 90%, more preferably about 100%, of that of thecorresponding dosage of amoxycillin taken as a conventional (immediaterelease) formulation, over the same dosage period, thereby maximisingthe absorption of the amoxycillin component from the slow releasecomponent.

The pharmcokinetic profile for a dosage of the present invention may bereadily determined from a single dosage bioavailability study in humanvolunteers. Plasma concentrations of amoxycillin may then be readilydetermined in blood samples taken from patients according to procedureswell known and documented in the art.

Representative modified release formulations include a tablet, includingswallow tablets, dispersible tablets, chewable tablets which may also beeffervescent and/or dispersible and, a capsule, granules or a sachet,typically a swallow tablet.

Representative modified release formulations having an immediate and aslow release phase provide a unit dosage in the range 700 to 1300 mg,preferably, 950 to 1300 mg, more preferably 850 to 1250 mg, amoxycillin,for instance unit dosages of 1000, 875 and 750 mg amoxycillin.Alternatively, and where the physical size of the dosage form is not aproblem, the unit dosage may provide the whole dosage, for instance asingle dosage sachet or dispersible tablet may comprise 1400 to 2600 mg,preferably, 1900 to 2600 mg, amoxycillin, for instance unit dosages of2000, 1750 and 1500 mg amoxycillin. It will be appreciated that such1000, 875 and 750 mg formulations are novel.

Accordingly, in a further aspect, the present invention provides for apharmaceutical formulation having an immediate release portion or phaseand a slow release portion or phase comprising:

(a) a unit dosage in the range 700 to 1300 mg, preferably, 950 to 1300mg, amoxycillin, for instance unit dosages of 1000, 875 or 750 mg±5%amoxycillin, or

(b) a unit dosage in the range 1400 to 2600 mg, preferably 1700 to 2600mg, more preferably 1900 to 2600 mg, amoxycillin, for instance unitdosages of 2000, 1750 or 1500 mg±5% amoxycillin,

in combination with pharmaceutically acceptable excipients or carriers.

Preferably, the ratio of amoxycillin in the immediate and slow releasephases is from 3:1 to 1:3, more preferably, from 2:1 to 2:3, yet morepreferably 3:2 to 1:1. Representative ratios include about 2:1, 9:7 or1:1. It is found useful to employ an excess of amoxycillin in theimmediate release phase, to ensure an adequate C_(max) value.

In the modified release formulations of the present invention, theportion of amoxycillin which is released immediately may be provided asamoxycillin trihydrate or an alkaline salt thereof, for instancepotassium or sodium amoxycillin, preferably, (crystallised) sodiumamoxycillin or a mixture thereof, preferably amoxycillin trihydrate;while the portion of amoxycillin which is released slowly is provided asamoxycillin trihydrate or an alkaline salt thereof, for instancepotassium or (crystallised) sodium amoxycillin or a mixture thereof,preferably (crystallised) sodium amoxycillin.

Preferably, the modified release formulation is a tablet. In a preferredmodified release tablet comprising 1000 mg amoxycillin, the immediaterelease phase comprises about 563 mg±5% amoxycillin trihydrate and theslow release phase about 438 mg±5% of amoxycillin, preferably as(crystallised) sodium amoxycillin.

In a representative modified release tablet of the present invention,the immediate release phase comprises about 438 mg amoxycillin,preferably amoxycillin trihydrate lanate and the slow release phaseabout 438 mg of amoxycillin, preferably (crystallised) sodiumamoxycillin, providing overall an 875 mg (14:1) tablet.

In a further representative tablet of the present invention, theimmediate release phase comprises about 500 mg amoxycillin and the slowrelease phase about 250 mg of amoxycillin, preferably (crystallised)sodium amoxycillin, providing overall a 750 mg (12:1) tablet.

It will be appreciated that the use of a mixture of amoxycillintrihydrate and sodium amoxycillin is more generally applicable to otherpharmaceutical formulations comprising amoxycillin.

Accordingly, in a further aspect, the present invention provides for apharmaceutical formulation comprising amoxycillin in which amoxycillinis provided as a mixture of amoxycillin trihydrate and sodiumamoxycillin in a ratio of from 3:1 to 1:3, more preferably 7:3 to 1:3,yet more preferably from 2:1 to 2:3, most preferably 3:2 to 1:1.Preferably the formulation comprises more than 500 mg amoxycillin, morepreferably at least 600 mg, most preferably at least 700 mg amoxycillin.Preferably, sodium amoxycillin is crystallised sodium amoxycillin.Representative formulation types include tablets, including immediaterelease and modified release tablets as herein described, as well asother solid dosage forms such as capsules, single dosage sachets andgranules. Representative tablets include those comprising 1000, 875, 500and 250 mg amoxycillin. Preferably, in modified release formulations ofthe present invention, the amoxycillin in the immediate release phaseconsists essentially of amoxycillin trihydrate and the amoxycillin ofthe slow release phase consists essentially of sodium amoxycillin.

For a tablet formulation, the immediate and slow release phases may beprovided in a number of different formats.

In a preferred aspect, the immediate and slow release phases areprovided as separate layers of a layered tablet.

Accordingly, in a further aspect, the present invention provides for alayered tablet comprising an immediate release layer comprisingamoxycillin and a slow release layer comprising amoxycillin and arelease retarding excipient which tablet:

(a) is a bilayered tablet;

(b) comprises at least three layers, including an immediate release anda slow release layer, and comprising at least 275 mg of amoxycillin inthe immediate release layer phase;

(c) comprises at least three layers, including an immediate release anda slow release layer, and in which the release retarding excipient inthe slow release layer comprises xanthan gum and/or a pharmaceuticallyacceptable organic acid; or

(d) comprises at least three layers, including an immediate release anda slow release layer, and in which the amoxycillin is provided as amixture of amoxycillin trihydatre and sodium amoxycillin, in a ratio of3:1 to 1:3.

As used herein, the term “bilayer” tablet refers to a tablet consistingof an immediate release and a slow release layer, optionally with acoating layer.

An immediate release layer may be, for example, a layer whichdisintegrates immediately or rapidly and has a composition similar tothat of known tablets which disintegrate immediately or rapidly. Forexample, the layer may comprise, in addition to the active materialcontent, excipients including diluents such as microcrystallinecellulose; disintegrants such as cross-linked polyvinylpyrrolidone(CLPVP), sodium starch glycollate; compression aids such as colloidalsilicon dioxide and microcrystalline cellulose; and lubricants such asmagnesium stearate. Such an immediate release layer may comprise around60 to 85% (all percentages given herein are on a weight percentage basisunless otherwise stated), preferably 70 to 85%, of active materialcontent, around 10 to 30%, preferably 10 to 20% of fillers/compressionaids, and conventional amounts of disintegrants and lubricants,typically about 0.5 to 3%, etc.

An alternative type of immediate release layer may be a swellable layerhaving a composition which incorporates polymeric materials which swellimmediately and extensively in contact with water or aqueous media, toform a water permeable but relatively large swollen mass. Activematerial content may be immediately leached out of this mass.

Slow release layers have a composition which comprises amoxycillintogether with a release retarding excipient which allows for slowrelease of amoxycillin. Suitable release retarding excipients include pHsensitive polymers, for instance polymers based upon methacrylic acidcopolymers such as the Eudragit (trade mark) polymers, for exampleEudragit L (trade mark) which may be used either alone or with aplasticiser; release-retarding polymers which have a high degree ofswelling in contact with water or aqueous media such as the stomachcontents; polymeric materials which form a gel on contact with water oraqueous media; and polymeric materials which have both swelling andgelling characteristics in contact with water or aqueous media.

Release retarding polymers which have a high degree of swelling include,inter alia, cross-linked sodium carboxymethylcellulose, cross-linkedhydroxypropylcellulose, high-molecular weighthydroxypropylmethylcellulose, carboxymethylamide, potassiummethacrylatedivinylbenzene co-polymer, polymethylmethacrylate,cross-linked polyvinylpyrrolidone, high-molecular weightpolyvinylalcohols etc.

Release retarding gellable polymers include methylcellulose,carboxymethylcellulose, low-molecular weighthydroxypropylmethylcellulose, low-molecular weight polyvinylalcohols,polyoxyethyleneglycols, non-cross linked polyvinylpyrrolidone, xanthangum etc.

Release retarding polymers simultaneously possessing swelling andgelling properties include medium-viscosity hydroxypropylmethylcelluloseand medium-viscosity polyvinylalcohols.

A preferred release-retarding polymer is xanthan gum, in particular afine mesh grade of xanthan gum, preferably pharmaceutical grade xanthangum, 200 mesh, for instance the product Xantural 75 (also known asKeltrol CR, Trade Mark, Monsanto, 800 N Lindbergh Blvd, St Louis, Mo.63167, USA). Xanthan gum is a polysaccharide which upon hydration formsa viscous gel layer around the tablet through which the active has todiffuse. It has been shown that the smaller the particle size, theslower the release rate. In addition, the rate of release of drugsubstance is dependent upon the amount of xanthan gum used and can beadjusted to give the desired profile. Controlled release formulationscomprising from 7.5 to 25% xanthan gum are described in EP 0 234 670A(Boots Co plc). The preferred embodiment is a tablet comprisingibuprofen as the drug substance and 15-20% xanthan gum, which is takenonce daily.

Examples of other polymers which may be used include Methocel K4M (TradeMark), Methocel E5 (Trade Mark), Methocel E5O (Trade Mark), Methocel E4M(Trade Mark), Methocel K15M (Trade Mark) and Methocel K100M (TradeMark). An example of a suitable polymer mixture is a mixture of MethocelE5 and K4M, for example 1:1, w:w.

Other known release-retarding polymers which may be incorporated includehydrocolloids such as natural or synthetic gums, cellulose derivativesother than those listed above, carbohydrate-based substances such asacacia, gum tragacanth, locust bean gum, guar gum, agar, pectin,carageenin, soluble and insoluble alginates, carboxypolymethylene,casein, zein, and the like, and proteinaceous substances such asgelatin.

Such a slow release layer may contain polymers which immediately swellin contact with water or aqueous media so that they form a relativelylarge swollen mass which is not immediately discharged from the stomachinto the intestine.

The slow release layer may also include diluents such as lactose;compression aids such as microcrystalline cellulose; and lubricants suchas magnesium stearate. The slow release layer may further comprisedisintegrants, such as cross-linked polyvinylpyrrolidone (CLPVP) andsodium starch glycollate; binders such as povidone(polyvinylpyrrolidone); desiccants, such as silicon dioxide; and solubleexcipients such as mannitol or other soluble sugars. Typically, the slowrelease layer comprises from about 60 to 80% by weight of amoxycillin;from 10 to 20% by weight of diluent/compression aid and from 1 to 2.5%by weight of lubricant.

When xanthan gum is used as the release-retarding polymer, the layercontains from 60 to 80% of amoxycillin, from 1 to 25%, preferably 2 to15%, more preferably 4 to 15% of xanthan gum, from 10 to 30%, preferably10 to 20% of fillers/compression aids, and conventional quantities oflubricants, all % being by weight of the layer. In a preferredembodiment, the slow release layer comprises from 70 to 80% ofamoxycillin, from 4 to 10%, of xanthan gum, from 10 to 20% ofmicrocrystalline cellulose, and from 1 to 2.5% of magnesium stearate,all % being by weight of the layer.

When release-retarding polymers other than xanthan gum are used, theslow release layer may contain around 30 to 70%, preferably from 40 to60%, of amoxycillin, from 15 to 45% of release-retarding polymer, from 0to 30% of fillers/compression aids, conventional quantities oflubricants, and from 5 to 20% of soluble excipients, all % being byweight of the layer.

It has also been surprisingly found that when the amoxycillin in theslow release layer is in the form of a soluble salt thereof, such assodium amoxycillin, then the release thereof may be retarded by theinclusion of an organic acid.

Accordingly, in a further aspect, the present invention provides for theuse of a pharmaceutically acceptable organic acid as a release retardingexcipient in a formulation comprising a pharmaceutically acceptablesoluble salt of amoxycillin, for instance sodium or potassiumamoxycillin, preferably sodium amoxycillin.

It will be appreciated that the use of an organic acid as a releaseretarding excipient is more generally applicable beyond the particularformulations hereinbefore described.

Accordingly, the present invention further provides for a pharmaceuticalformulation comprising a pharmaceutically acceptable soluble salt ofamoxycillin, for instance sodium amoxycillin, in a slow release phasewhich further comprises a release retarding excipient which is apharmaceutically acceptable organic acid present in a molar ratio offrom 100:1 to 1:10, preferably 50:1 to 1:5, more preferably 20:1 to 1:2(amoxycillin to organic acid).

It is believed that intimate contact between the organic acid and thesalt of amoxycillin in the pharmaceutical formulation, for instance as aconsequence of compacted granule formation or direct compression in atablet, causes some form of interaction which modifies the release ofthe amoxycillin component from the formulation.

Soluble pharmaceutically acceptable salts of amoxycillin include alkalimetal salts such as sodium and potassium; alkaline earth metal saltssuch as magnesium and calcium, and acid salts such as amoxycillinhydrochloride. Preferably, the salt is sodium amoxycillin, morepreferably crystallised sodium amoxycillin.

As used herein, the term “pharmaceutically acceptable organic acid”shall mean organic acids which are without pharmacological effect perse, have acceptable organoleptic properties, have acceptable density, donot have an extreme pH and are preferably solid. Examples thereofinclude mono-carboxylic acids and poly-carboxylic acids having from 2 to25, preferably from 2 to 10, carbon atoms; monocyclic and polycyclicaryl acids such as benzoic acid; as well as monohydrogen, dihydrogen etcmetal salts of multi-valent acids. A single pharmaceutically acceptableorganic acid may be used, or two or more of such may be used incombination. Preferably, the organic acid is a C₍₂₋₁₀₎alkyl- oralkenyl-carboxylic acid having from one, two or three carboxylic acidgroups, and optionally with one or more hydroxy substituents or anadditional CO group in the carbon chain, for instance malonic acid,succinic acid, fumaric acid, maleic acid, adipic acid, lactic acid,levulinic acid, sorbic acid or a fruit acid such as tartaric acid, malicacid, ascorbic acid or citric acid, or an acidic salt thereof, morepreferably anhydrous citric acid.

The organic acid may be used alone or in combination with a releaseretarding polymer as hereinbefore described. A preferred combinationcomprises citric acid and a release retarding gellable polymer, inparticular xanthan gum. In the presence of the organic acid, forinstance citric acid, xanthan gum may be used at a lower level then whenincluded on its own, for instance, from 0.5 to 8%, preferably 1 to 5%,typically about 2%, by weight of the slow release layer.

When an organic acid is used as a release-retarding excipient, the slowrelease layer contains from 60 to 80% of a soluble salt of amoxycillin,from 10 to 30%, preferably 10 to 20% of fillers/compression aids, andconventional quantities of lubricants, all % being by weight of thelayer. In a preferred embodiment, the slow release layer comprises from60 to 70% of a soluble salt of amoxycillin, from 10 to 20% ofmicrocrystalline cellulose, and from 1 to 2.5% of magnesium stearate,all % being by weight of the layer.

In a representative example, a layered tablet comprises in the slowrelease layer crystallised sodium amoxycillin and citric acid, in amolar ratio of about 50:1 to 1:2, preferably 20:1 to 1:2, morepreferably 2:1 to 1:1.2, yet more preferably about 1:1. In a preferredembodiment, the slow release layer comprises about 438 mg±5%crystallised sodium amoxycillin, about 78 mg±10% citric acid and about2% by weight of xanthan gum.

In a preferred layered tablet comprising 1000 mg amoxycillin, theimmediate release layer comprises about 563 mg±5% amoxycillin,preferably amoxycillin trihydrate, and the slow release layer about 438mg±5% of a soluble salt of amoxycillin, preferably crystallised sodiumamoxycillin, about 78 mg±10% citric acid and about 2% by weight ofxanthan gum.

The tablet formulations of the invention may also include one or morebarrier layers, which may be located between the respective first andsecond layers, and/or on one or more of the outer surfaces of the firstand second layers, for example the end faces of the layers of asubstantially cylindrical tablet. Such barrier layers may, for example,be composed of polymers which are either substantially or completelyimpermeable to water or aqueous media, or are slowly erodable in wateror aqueous media or biological liquids and/or which swell in contactwith water or aqueous media. Suitably the barrier layer should be suchthat it retains these characteristics at least until complete orsubstantially complete transfer of the active material content to thesurrounding medium.

Suitable polymers for the barrier layer include acrylates,methacrylates, copolymers of acrylic acid, celluloses and derivativesthereof such as ethylcelluloses, cellulose acetate propionate,polyethylenes and polyvinyl alcohols etc. Barrier layers comprisingpolymers which swell in contact with water or aqueous media may swell tosuch an extent that the swollen layer forms a relatively large swollenmass, the size of which delays its immediate discharge from the stomachinto the intestine. The barrier layer may itself contain active materialcontent, for example the barrier layer may be a slow or delayed releaselayer. Barrier layers may typically have an individual thickness of 2 mmto 10 microns.

Suitable polymers for barrier layers which are relatively impermeable towater include the Methocel (trade mark) series of polymers mentionedabove, for example Methocel K100M, Methocel K15M, Methocel E5 andMethocel E50, used singly or combined, or optionally combined with anEthocel (trade mark) polymer. Such polymers may suitably be used incombination with a plasticiser such as hydrogenated castor oil. Thebarrier layer may also include conventional binders, fillers, lubricantsand compression acids etc such as Polyvidon K30 (trade mark), magnesiumstearate, and silicon dioxide, e.g. Syloid 244 (trade mark).

The tablet formulation of the invention may be wholly or partly coveredby a coating layer, which may be a protective layer to prevent ingressof moisture or damage to the tablet. The coating layer may itselfcontain active material content, and may, for example, be an immediaterelease layer, which immediately disintegrates in contact with water oraqueous media to release its active material content, for exampleamoxycillin and potassium clavulanate. Preferred coating materialscomprise hydroxypropylmethylcellulose and polyethylene glycol, with Atitanium dioxide as an opacifying agent, for instance as described in WO95/28927 (SmithKline Beecham).

As well as active material content etc, the tablet of the invention mayalso include a pH modifying agent, such as a pH buffer, which may becontained in either the immediate-, or slow-release layers, or in acoating around all or part of the tablet. A suitable buffer is calciumhydrogen phosphate.

In a tablet without a barrier layer, the immediate release layercomprises form 50 to 60% and the slow release layer comprises from 40 to50% of the overall tablet weight. When a barrier layer is present, theimmediate release layer typically comprises from 40 to 50%, the slowrelease layer comprises from 35 to 45%, and the barrier layer comprisesfrom 5 to 20% of the overall tablet weight.

It is found that a satisfactory pharmacokinetic profile may be obtainedfrom a bilayered tablet of the present invention without the need toinclude a barrier layer. Accordingly, a bi-layer tablet is preferred.This also reduces the complexity of the manufacturing process.

It will be appreciated that 1000, 875 and 750 mg layered tablets havingan immediate release layer and a slow release layer are novel.Accordingly, in a further aspect, the present invention provides for apharmaceutical layered tablet formulation comprising an immediaterelease layer and a slow release layer and comprising from 700 to 1250mg amoxycillin, preferably 1000, 875 or 750 mg±5% amoxycillin, incombination with pharmaceutically acceptable excipients or carriers.Preferably, the layered tablet is a bi-layered tablet.

Suitably the tablet formulations of the invention may be formed by knowncompression tabletting techniques, for example using a known multi-layertabletting press. Preferably, in a preliminary step, slugging or rollercompaction is used to form granulates. Lubricants and compression aids(if used) are then added, to form a compression blend for subsequentcompaction.

Preferred bilayer tablets of the present invention may be made by aprocess which comprises as, an early phase, the formation of slowrelease compacted granules, comprising the steps of blending togethersodium amoxycillin, a diluent/compression aid such as microcrystallinecellulose, a portion of the lubricant (between 40 and 60%, typicallyabout 50%) and a pharmaceutically acceptable organic acid such as afruit acid, for instance citric acid, or a release retarding polymersuch as xanthan gum or a mixture thereof, compacting the blend, forinstance in a roller compactor or by slugging, and then milling, to formslow release granules. Preferably such granules have a size in the range100 to 1000 microns. The incorporation of xanthan gum appears to alsohave an unexpected benefit on processibility.

Such slow release compacted granules may then be blended with otherexcipients such as magnesium stearate, to form a slow releasecompression blend.

In addition, amoxycillin trihydrate, microcrystalline cellulose, adisintegrant such as sodium starch glycollate and a lubricant such asmagnesium stearate, are blended together, compacted, for instance in aroller compactor or by slugging, and then milled to form immediaterelease compacted granules. These immediate release compacted granulesmay then be blended with other excipients such as magnesium stearate andcolloidal silica, to form an immediate release compression blend.

The immediate release and slow release compression blends may then becompressed as separate layers on a bilayer tablet press, to form bilayertablets.

Such slow release granules are novel. Accordingly, in a further aspect,the present invention provides for compacted granules comprising asoluble salt of amoxycillin, for instance sodium amoxycillin, adiluent/compression aid, and an organic acid or a release retardingpolymer or a mixture thereof, as hereinbefore defined. In a yet furtheraspect, the present invention also provides for compacted granulescomprising amoxycillin trihydrate, a diluent/compression aid, and arelease retarding polymer, as hereinbefore defined.

Alternatively, a dry densification process may be used, e.g.briquetting. Typically the active material content, pH modifiers,buffers, fillers and/or diluent, release retarding agents, disintegrantsand binders, when used are mixed, then lubricants and compression aidsare added. The complete mixture may then be compressed under highpressure in the tablet press. A wet granulation process may be also beused, for instance with isopropanol as the solvent and Polyvidon K-30(trade mark) as the wet granulating aid.

A barrier layer, if present, may typically be made up by a wetgranulation technique, or by dry granulation techniques such as rollercompaction. Typically the barrier material, e.g. Methocel (trade mark)is suspended in a solvent such as ethanol containing a granulation acidsuch as Ethocel or Polyvidon K-30 (trade mark), followed by mixing,sieving and granulation. Typically a first layer may be formed, then abarrier layer deposited upon it, e.g. by compression, spraying orimmersion techniques, then the second layer may be formed so that thebarrier layer is sandwiched between the first and second layers.Additionally, or alternatively, the first and second layers may beformed and a barrier layer may then be formed, for instance bycompression, spraying or immersion, on one or more of the end faces ofthe tablet.

Tablet cores may then be coated with a coating layer which may beapplied from an aqueous or an organic solvent system, preferably anaqueous solvent system, to provide film coated tablets.

The invention also provides a method for the manufacture of a tabletformulation as described above comprising the steps of forming saidfirst and second layers, and any barrier layers and coating layer(s)which may be present.

In addition to the layered tablet approach hereinbefore described, othertypes of tablet may be used to provide an immediate release phase and aslow release phase, using the excipients hereinbefore described butproviding the phases in different formats. Thus, the slow release phasemay form the core of a tablet which is then surrounded by an outercasing forming the immediate release phase, optionally with anintermediate coating layer around the core and/or a final coating layeraround the outer casing (see WO 95/28148, SmithKline Beecham). The slowrelease phase may also be provided as granules which are dispersed in amatrix of amoxycillin, the matrix forming the immediate release phase(see WO 96/04908, SmithKline Beecham).

In a further variant, a monolith modified release tablet may be preparedfrom slow release compacted granules comprising amoxycillin, adiluent/compression aid such as microcrystalline cellulose, and apharmaceutically acceptable organic acid such as a fruit acid, forinstance citric acid (if amoxycillin is present as a soluble saltthereof), or a release retarding polymer such as xanthan gum or amixture thereof, preferably a release retarding polymer (as hereinbeforedescribed); and immediate release compacted granules comprisingamoxycillin (as hereinbefore described) the granules being combined withextragranular excipients to form tablets. Such granules may also beprocessed into other pharmaceutical formulations, for instance singledosage sachets, capsules or chewable tablets comprising a unit dosage ashereinbefore described.

Chewable tablets according to the present invention typically comprise achewable base formed from, for instance, mannitol, sorbitol, dextrose,fructose or lactose alone or in combination. A chewable tablet may alsocomprise further excipients, for instance, disintegrants, lubricants,sweetening agents, colouring and flavouring agents. Such furtherexcipients together will preferably comprise from 3 to 10%, morepreferably 4 to 8%, yet more preferably 4 to 7% by weight of the tablet.Disintegrants may be present in from 1 to 4%, preferably from 1 to 3%,more preferably from 1 to 2% by weight of the tablet. Representativedisintegrants include crospovidone, sodium starch glycollate, starchessuch as maize starch and rice strach, croscarmellose sodium andcellulose products such as microcrystalline cellulose, microfinecellulose, low substituted hydroxy propyl cellulose, either used singlyor in admixture. Preferably, the disintegrant is crospovidone.Lubricants may be present in from 0.25 to 2.0%, preferably from 0.5 to1.2% by weight of the tablet. Preferred lubricants include magnesiumstearate. Preferably, the sweetening agent is an artificial sweeteningagent such as sodium saccharin or aspartame, preferably aspartame, whichmay be present in from 0.5 to 1.5% by weight of the tablet. Preferably,a tablet of the present invention is substantially free of sugar(sucrose). Preferred flavouring agents include fruit flavours which maybe natural or synthetic, for instance peppermint, cherry and banana, ora mixture thereof.

Single dose sachets according to the present invention comprise, inaddition to the drug substance, excipients typically included in asachet formulation, such as a sweetener, for instance aspartame,flavourings, for instance fruit flavours, as well as silica gel, to actas a desiccant.

Capsules according to the present invention comprise, in addition to thedrug substance, excipients typically included in a capsule, for instancestarch, lactose, microcrystalline cellulose, magnesium stearate.Preferably, capsules are prepared from materials such as HPMC orgelatin/PEG combination.

A process for the preparation of crystallised sodium amoxycillin isdescribed in EP-A-0 131 147 (Beecham Group plc).

In a further embodiment, the slow release phase may be provided as aseparate component, for instance as a separate tablet, so that the unitdosage is provided as a combination of a conventional component in whichamoxycillin is released immediately, and a further formulation, forinstance a tablet, comprising amoxycillin from which amoxycillin isreleased slowly. The combined weights of amoxycillin in the conventionaland slow release formulations will provide the overall unit dosage.Thus, for instance a dosage of 2000 mg may be provided by a combinationof two existing 500 mg amoxycillin tablets in combination with a slowrelease tablet comprising 1000 mg of amoxycillin. Furthermore, a dosageof 1750 mg may be provided by an existing 875 mg tablet (SmithKlineBeecham) in combination with a slow release tablet comprising 875 mg ofamoxycillin. In addition, a dosage of 1500 mg may be provided by twoexisting 500 mg tablets of amoxycillin in combination with a slowrelease tablet comprising 500 mg of amoxycillin. Accordingly, in afurther aspect, the present invention provides for a kit comprising aconventional (immediate release) tablet comprising amoxycillin, and aslow release tablet comprising amoxycillin.

In a further aspect, the present invention provides for a slow releasepharmaceutical formulation, preferably a tablet, comprising amoxycillin(as the sole active ingredient) formulated with a release retardingexcipient which causes a slow release of the amoxycillin from theformulation, and excluding; tablets which comprise 750 mg or less ofamoxycillin in which the amoxycillin is present essentially asamoxycillin trihydrate; or tablets comprising from 400 to 500 mgamoxycillin in which amoxycillin is present as a mixture comprising atleast 70% amoxycillin trihydrate and up to 30% sodium amoxycillin incombination with hydroxypropyl methylcellulose as a release retardingexcipient.

Such formulations may comprise from 100 to 1250 mg amoxycillin which maybe amoxycillin trihydrate or (crystallised) sodium amoxycillin or amixture thereof, for instance 500, 875 or 1000 mg amoxycillin. Suitableexcipients for slow release are those hereinbefore described for slowrelease layers. The formulation may comprise from 1 to 25%, preferablyfrom 2 to 15%, more preferably 4 to 10% of xanthan gum, or from 10 to25, preferably 15 to 20% of a hydroxypropylmethylcellulose, for instanceMethocel K100LV or Methocel K4M. Alternatively, such formulations maycomprise citric acid, optionally with xanthan gum, as hereinbeforedescribed.

Preferably, the unit dosage forms of the present invention are packagedin containers that inhibit the ingress of atmospheric moisture, forinstance blister packs, tightly closed bottles or desiccated pouch packsetc which are conventional in the art. Preferably, bottles also includea desiccating material, to preserve the clavulanate. Preferred bottlesinclude HDPE bottles. Preferred blister packs include cold-formedblister packs in which each blister may contain one tablet, or twotablets, where the unit dosage is two tablets, for instance 2×1000/62.5mg tablets, to improve patient compliance.

It will be appreciated that the present application relates toinventions in which the drug substance consists essentially ofamoxycillin and does not extend inventions in which the drug substanceis amoxycillin in combination with potassium clavulanate.

The invention will now be described by way of example only withreference to the accompanying drawings, in which:

FIG. 1 shows the structure of various types of layered tablets of thepresent invention, in particular the structure of substantiallycylindrical compressed tabletys are shown in longitudinal section. InFIG. 1A, the tablet comprises a first layer (1) and a second layer (2),without any barrier layer or coating layer. In FIG. 1B, the tabletcomprises a first layer (1), a second layer (2), and a barrier layer (3)sandwiched between the first and second layers (1) and (2). In FIG. 1C,the tablet comprises a first layer (1), a second layer (2), and abarrier layer (3) located on the end face of the second layer (2). InFIG. 1D, the tablet comprises a first layer (1), a second layer (2), abarrier layer (3) sandwiched between the first and second layers (1) and(2), and a coating layer (4) which partly covers the tablet. The dottedline shows the possibility of the coating layer (4A) covering the entiretablet. In FIG. 1E, the tablet comprises a first layer (1) a secondlayer (2), and a third layer (3) intermediate between the first andsecond layers (1) and (2). All three of these layers (1), (2) and (3)include active material content.

All publications and references, including but not limited to patentsand patent applications, cited in this specification are hereinincorporated by reference in their entirety as if each individualpublication or reference were specifically and individually indicated tobe incorporated by reference herein as being fully set forth. Any patentapplication to which this application claims priority is alsoincorporated by reference herein in its entirety in the manner describedabove for publications and references.

EXAMPLE 1 1000 mg Modified Release Tablet

mg/table % Name of Ingredient t w/w Immediate Release Layer AmoxycillinTrihydrate 654.1* 40.88 Microcrystalline Cellulose 216.6 13.28 SodiumStarch Glycollate 18.0 1.12 Colloidal Silicon Dioxide 6.3 0.39 MagnesiumStearate 9.0 0.56 Total (Immediate Release Layer) 900.0 56.23 SlowRelease Layer Sodium Amoxycillin 480.8** 30.05 MicrocrystallineCellulose 113.2 7.08 Xanthan Gum 14.0 0.87 Citric Acid (anhydrous) 78.04.87 Colloidal Silicon Dioxide 1.5 0.09 Magnesium Stearate 14.0 0.87Total (Sustained Release Layer) 700.0 43.74 Film coat - Opadry YS-1-7700Composition Hydroxypropylmethylcellulose 2910 6 cp 11.6Hydroxypropylmethylcellulose 2910 15 cp 3.9 Titanium dioxide 15.1Polyethylene Glycol 3350 2.3 Polyethylene Glycol 8000 2.3 Total weightof coated tablet 1635.2 * Equivalent to 562.5 mg of amoxycillin based onan assay of 86.0% **Equivalent to 437.5 mg amoxycillin based on an assayof 91.0%

EXAMPLE 2 1000/62.5 mg Modified Release Tablet

The immediate release layer and film coat are as for the tablet ofExample 1

Name of Ingredient mg/tablet % w/w Slow Release Layer Sodium Amoxycillin480.8** 30.05 Microcrystalline Cellulose 127.2 7.95 Citric Acid(anhydrous) 78.0 4.87 Colloidal Silicon Dioxide 1.5 0.09 MagnesiumStearate 14.0 0.87 Total (Slow Release Layer) 700.0 43.74 Total Weightof coated tablet 1635.2 **Equivalent to 437.5 mg amoxycillin based on anassay of 91.0%

Preparation of Modified Release Tablets

Amoxycillin trihydrate and microcrystalline cellulose (about 90% of thetotal) were milled and screened and then blended with magnesiumstearate. This blend was roller compacted, using a Chilsonater, andmilled to form immediate release granules. The remaining magnesiumstearate and microcrystalline cellulose, sodium starch glycollate andcolloidal silicon dioxide were then milled and screened and added tothese granules and blended to form the immediate release compressionblend.

Crystallised sodium amoxycillin microcrystalline cellulose (about 70% ofthe total) and anhydrous citric acid were milled and blended withxanthan gum (if applicable), magnesium stearate (about 70% of the total)and colloidal silicon dioxide. This blend was then roller compacted in aChilsonator, and milled to form slow release granules. The remainingmagnesium stearate and microcrystalline cellulose were added to thesegranules and blended to form the slow release compression blend.

The two blends were then compressed as separate layers in a bilayertablet press equipped with punches measuring 0.0406 inches by 0.8730inches and having a modified capsule shape.

Finally, the tablet cores were coated with an aqueous film coating,using a 15% solids aqueous suspension, in a 60 inch coating equippedwith 4 spray guns.

EXAMPLE 3 Slow Release Tablet (875 Mg)

mg/tablet % (a) Sodium Amoxycillin Tablet Crystallised SodiumAmoxycillin 91%* 961.54 73.96 Dried Microcrystalline Cellulose 273.4621.04 Magnesium Stearate 13.0 1.00 Xanthan gum 200 mesh** 52.0 4.00Total 1300 100 (b) Sodium Amoxycillin Tablet with citric acidCrystallised Sodium Amoxycillin 91%* 961.54 66.31 Dried MicrocrystallineCellulose 288.96 19.92 Magnesium Stearate 14.50 1.00 Citric acid(anhydrous) 156 10.75 Xanthan gum 200 mesh** 29.0 2.00 Total 1450 100(c) Amoxycillin Trihydrate Tablet Amoxycillin Trihydrate 86%* 1017.478.26 Dried Microcrystalline Cellulose 217.6 16.74 Magnesium Stearate13.0 1.00 Xanthan Gum, 200 mesh** 52.0 4.00 Total 1300 100 * adjustedfor the potency of the amoxycillin component and corresponding to 875 mgamoxycillin, ** Xantural 75

EXAMPLE 4 875 Mg Modified Release Tablet Slow Release Layer

This may be formed using half the quantities given above, for a slowrelease layer comprising about 438 mg amoxycillin.

Immediate release layer - 1 Amoxycillin trihydrate 507 mg (equiv toamoxycillin free acid) (438) Microcrystalline cellulose (Avicel PH102)196.8 Sodium starch glycollate (Explotab)  26 Magnesium stearate  6.5Immediate release layer - 2 Amoxycillin trihydrate 507 mg (equiv toamoxycillin free acid) (438) Microcrystalline cellulose (Avicel PH102)206 Sodium starch glycollate (Explotab)  34 Talc  67 Magnesium stearate 25 Silica (Syloid)  17

Barrier Layers

Barrier layers and methods for their preparation are described in WO95/20946 (SmithKline Beecham).

Preparation of Tablets

The active ingredients, fillers and diluents (microcrystallinecellulose), release controlling agents (if present), disintegrants(crospovidone, sodium starch glycollate) etc are mixed. Lubricants(talc, Mg-stearate) and colloidal silicon dioxide (Syloid 244) areadded, and mixing is continued for another minute. The complete mixtureis slugged on a tablet press or roller compacted (briquetting step),followed by size reduction (Apex, Fitzmill, Frewitt) and passage throughan oscillatory sieve or particle size classifier (Kason, Sweco). If theflow properties are unsatisfactory, the briquetting step is repeated.Separate compressed blends are prepared for the immediate and slowrelease layers, and barrier layer, if present.

In some cases, where the bulk density is rather low, a densifying step(pre-tabletting and sieving as in the briquetting method) may berequired in order to achieve the nominal weight of a particular layer.

The blends are then compressed as separate layers on a layer tabletpress to form bilayered tablets. Tablets may then be coated with a whiteopaque coating, for instance the product Opadry, Opaspray (Colorcon).

Example 5 Dissolution Testing Methods

The release of amoxycillin from tablets into static media was measuredusing the <711> Dissolution Test, Apparatus 2, provided in USP 23, 1995.

Test specifications: Temperature: 37.0 ± 0.50° C. Medium: Deionizedwater, 900 mL Paddle speed 75 rpm

Method

Aliquots of medium were removed for assay after 15, 30, 45, 60, 90, 120,150, 180, 240, 300 360, 420 and 480 min, each aliquot being replacedsimultaneously by an equal volume of medium to maintain constant volume.The amount of drug substance was determined by UV spectrometry, at 272nM. The resulting dissolution profile for the tablets of Example 1 and 2are shown as FIG. 2.

In Vivo Pharmacokinetic Evaluation of Formulations

The bioavailability of dosages comprising amoxycillin and potassiumclavulante were evaluated in two human volunteer studies, Study A andStudy B. It was not anticipated that the presence of potassiumclavulanate would affect the performance of the amoxycillin component.

The two studies were open, randomised, crossover studies in healthyvolunteers. Each dosage was administered with the aid of approximately200 mL water, at the start of a light breakfast and after an overnightfast. Blood samples were collected into tubes containing EDTA at nominaltimes of pre-dose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10 and 12 hafter start of dosing, for assay of plasma levels of amoxycillin andclavulanate. Samples were cooled in an ice-bath awaiting furtherprocessing. Plasma was separated by refrigerated centrifugation at 4° C.and transferred to appropriately labelled polypropylene specimencontainers and stored frozen at approximately −70° C. until assayed.

Samples were assayed for amoxycillin using a method based on proteinprecipitation with acetonitrile. Amoxycillin was extracted from humanplasma (50 μL) by means of protein precipitation, using acetonitrilecontaining the internal standard and quantified by LC/MS/MS.Specifically, human plasma (50 μL) was pipetted into a 1.5 mL Eppendorftube followed by the addition of acetonitrile containing the internalstandard ([¹³C₆]-amoxycillin, 200 μL). The tube was capped, vortex mixedand shaken for approximately 15 minutes. After centrifuging the sample(approximately 11,000×g, for 15 minutes), the supernatant wastransferred to a silanised 1.1 mL tapered autosampler vial containing200 μL of 5 mM ammonium acetate solution. An aliquot of extract wasinjected onto the HPLC/MS/MS system for analysis. The mass spectrometerwas operated in positive ion mode, employing a Turbo IonSpray interface.Multiple reaction monitoring (MRM) was used to detect the components,amoxycillin and [¹³C₆]-amoxycillin. The MRM procedure involves (1) massselection of a characteristic ion of the required drug or internalstandard in the first quadrupole mass analyser (2) fragmentation of theselected ion in the instrument's collision cell (3) detection of afragment ion which is characteristic of the compound of interest.Quantification is performed by comparison of the chromatographic peakareas of the drug relative to the area of the internal standard. Linearresponses in the analyte/internal standard peak area ratios wereobserved for analyte concentrations ranging from 0.05 μg/mL (lower limitof quantification; LLQ) to 10 μg/mL (upper limit of quantitication:ULQ). QC samples were assayed with each batch of samples againstseparately prepared calibration standards. The results of the QC sampleswere used to assess the day-to-day performance of the assay.

Plasma concentration-time data for each subject in each regimen wereanalysed by non-compartmental methods using the non-compartmentalpharmacokinetic analysis program WinNonlin Professional Version 1.5. Allcalculations were based on actual sampling times. Pharmacokineticparameters determined included maximum observed plasma concentration(Cmax) and time to reach maximum plasma concentration (Tmax). Theapparent terminal elimination rate constant (lz) was derived from thelog-linear disposition phase of the concentration-time curve usinglinear least-squares regression with visual inspection of the data todetermine the appropriate number of points to calculate lz. The apparentterminal elimination half-life (T½) was calculated as ln(2)/lz.

Area under the plasma concentration-time curve from time zero to thelast quantifiable plasma concentration [AUC(0-t)] was determined usingthe linear trapezoidal rule for each incremental trapezoid and the logtrapezoidal rule for each decremental trapezoid [Chiou W L., J.Pharmacokinet. Biopharm., 1978, 6, 539-547]. The area under the plasmaconcentration-time curve extrapolated to infinity [AUC(0-inf)] wascalculated as the sum of AUC(0-t) and C(t)/lz, where C(t) was thepredicted concentration from the log-linear regression analysis at thelast measurable time point.

The time above the minimum inhibitory plasma concentration (T>MIC) wascalculated manually by graphical interpolation, where the minimuminhibitory plasma concentrations was defined as 4 μg/mL for amoxycillin.

The mean concentration-time profiles for amoxycillin was derived at eachnominal sampling time for each formulation. In cases where a post-dosevalue was not quantifiable, a value of ½ the LLQ (0.050 μg/mL) wasassigned to determine the mean value. Where the calculated mean valuewas less than the LLQ or was based on greater than 50% NQ values, avalue of NQ was assigned for that sampling time.

Log_(e)-transformed Cmax and untransformed T>MIC for each of theformulations were analysed using Analysis of Covariance (ANCOVA) fittinga single term for formulation and fitting the data from the referenceformulation as a co-variate. The 95% confidence intervals for the meansof each formulation were constructed using the residual variance fromthe model. For Cmax, the confidence interval estimates on the log scalewere then back-transformed to obtain the 95% confidence intervals of thegeometric mean. These results were displayed graphically.

Assumptions underlying the analyses were assessed by inspection ofresidual plots. Homogeneity of variance was assessed by plotting thestudentised residuals against the predicted values from the model, whilenormality was assessed using normal probability plots. Particularattention was paid to any outlying values observed with the referenceformulation.

Study A

The first study compared three modified release dosages of 1750/125 mg(formulations I to III) and a fourth modified release dosages of1500/125 mg (formulation IV) against an immediate release dosage of1750/125 mg (formulation V), as follows:

(a) a dosage of 1750/125 mg amoxycillin/potassium clavulanate, made upof a combination of one modified release tablet comprising 875/125 mgamoxycillin trihydrate/clavulanate and 4% xanthan gum and one immediaterelease tablet comprising 875 mg amoxycillin trihydrate (formulation I);

(b) a dosage of 1750/125 mg amoxycillin/potassium clavulanate, made upof a combination of one modified release tablet comprising 875/125 mgcrystallised sodium amoxycillin/clavulanate and 4% xanthan gum and oneimmediate release tablet comprising 875 mg amoxycillin trihydrate(formulation II);

(c) a dosage of 1750/125 mg amoxycillin/potassium clavulanate, made upof a combination of one modified release tablet comprising 875/125 mgcrystallised sodium amoxycillin/clavulanate, citric acid (156 mg) and 2%xanthan gum and one immediate release tablet comprising 875 mgamoxycillin trihydrate (formulation M);

(d) a dosage of 1500/125 mg amoxycillin/potassium clavulanate (made upof a modified release tablet comprising 500/125 mg crystallised sodiumamoxycillin/potassium clavulanate and two immediate release tabletcomprising 500 mg amoxycillin tribydrate (Amoxyl, SmithKline Beecham)(formulation IV); and

(e) a dosage of 1750/125 mg amoxycillin/potassium clavulanate, made upof a combination of one immediate release tablet comprising 875/125 mgamoxycillin trihydrate/clavulanate (Augmentin, SmithKline Beecham) andone immediate release tablet comprising 875 mg amoxycillin trihydrate(Amoxyl, SmithKline Beecham) (formulation V).

Results Formulation n Cmax¹ T > MIC^(1,2) AUC^(1,3) I 8 12.75 (4.96) 4.5(1.8) 47.83 II 8 18.56 (4.72) 4.4 (1.0) 57.46 III 8 13.03 (2.34) 5.73(2.54)  54.93 IV 8 17.33 (4.66) 4.8 (0.9) 56.71 V 40 20.21 (6.09) 4.2(0.9) 56.33 () standard deviation ¹arithmetic mean value ²T > MIC is thetime (h) above an amoxycillin concentration of 4 μg/ml ³Area under thecurve (0 to 12 h, μg.h/mL)

The pharmacokinetic profile is shown in FIG. 3.

Study B

The second study investigated two different modified release dosages of2000/125 mg (formulations VI and VII) against an immediate releasedosage of 2000/125 mg (formulation VI), as follows:

(a) a dosage of 2000/125 mg amoxycillin/potassium clavulanate, made upof two bilayer tablets according to Example 1 (formulation VI);

(b) a dosage of 2000/125 mg amoxycillin/potassium clavulanate, made upof two bilayer tablets according to Example 2 (formulation VII);

(c) a dosage of 2000/125 mg amoxycillin/potassium clavulanate, made upof a combination of three tablets each comprising 500 mg amoxycillin(Amoxyl, SmithKline Beecham) and one tablet comprising 500 mgamoxycillin and 125 mg potassium clavulanate (Augmentin, SmithKlineBeecham) (formulation VIII).

Results Formulation N Cmax¹ T > MIC^(1,2) T > MIC^(1,3) AUC^(1,4) VI 717.41 (1.93) 6.0 (1.3) 4.8 (1.2) 74.9 VII 8 17.46 (6.02) 5.9 (1.3) 4.0(1.3) 71.5 VIII 12 23.75 (5.73) 4.9 (1.1) 3.5 (1.0) 69.2 () standarddeviation ¹arithmetic mean value ²T > MIC is the time (h) above anamoxycillin concentration of 4 μg/ml ³T > MIC is the time (h) above anamoxycillin concentration of 8 μg/ml ⁴Area under the curve (0 to 12 h,μg.h/mL).

Comparison of the AUC values for formulations VI and VII (bilayertablets) against VIII (immediate release tablets) shows that theabsorption of the amoxycillin component has not been compromised byformulating a part of it in a slow release layer. This means that thereis no extra, unabsorbed amoxycillin which may otherwise cause problemsfurther down in the GI tract, for instance due to a lack of absorptionand destruction of symbiotic bacteria.

It was also found that for formulation VL there was less inter-subjectvariability in the amoxycillin plasma concentrations than forformulation VII. These formulations were the same, except thatformulation VI also comprised xanthan gum (2%) in the slow releaselayer.

The pharmacokinetic profile for amoxycillin plasma concentration isshown in FIG. 4 (in which A is formulation VI, B is formulation VII, Dis formulation VIII).

The present invention also extends to formulations which arebioequivalent to the tablets of formulations VI and VII, in terms ofboth rate and extent of absorption, for instance as defined by the USFood and Drug Administration and discussed in the so-called “OrangeBook” (Approved Drug Products with Therapeutic Equivalence Evaluations,US Dept of Health and Human Services, 19th edn, 1999).

Reference Data

The existing Augmentin 875/125 mg tablet has a C_(max) value of 11.6±2.8μg/ml (Physicians Desk Reference, Medical Economics Co, 52 edition,1998, 2802). The time above MIC was about 40% of the 12 hour dosinginterval for an MIC of 2 μg/ml and about 30% for an MIC of 4 μg/ml(SmithKline Beecham data).

What is claimed is:
 1. A method of treating a bacterial infection in ahuman in need thereof which method comprises administering to said humana dosage of a therepeutically effective amount of amoxycillin in therange of 1900 to 2600 mg, at a dosage regimen interval of about 12 h,and wherein the infection is caused by the organism S pneumoniae(including Drug Resistant and Penicillin Resistant S pneumoniae), Hinfluenzae, M catarrhalis and/or S pyogenes.
 2. The method according toclaim 1 in which the dosage regimen provides a mean plasma concentrationof amoxycillin of 4 μg/mL for at least 4.4 h and a mean maximum plasmaconcentration (C_(max)) of amoxycillin of at least 12 μg/mL.
 3. Themethod according to claim 1 in which the dosage regimen provides a meanplasma concentration of amoxycillin of 4 μg/mL for at least 4.8 h and amean maximum plasma concentration (C_(max)) of amoxycillin of at least16 μg/mL.
 4. The method according to claim 1 in which the dosage regimenprovides a mean plasma concentration of amoxycillin of 8 μg/mL for atleast 4.4 h.
 5. The method according to claim 1 in which the dosage isdelivered from an immediate release formulation.
 6. The method accordingto claim 5 in which the dosage is 2000, 2250 or 2500 mg of amoxycillin.7. The method according to claim 6 in which the dosage is provided as asingle tablet, or as a number of smaller tablets, may be the same ordifferent.
 8. The method according to claim 1 in which the dosage isdelivered from a modified release formulation.
 9. The method accordingto claim 8 in which the dosage is provided as a number of tablets, whichmay be the same or different.
 10. The method according to claim 8 inwhich the dosage is 2000, 2250 or 2500 mg of amoxycillin.
 11. A methodof treating a bacterial infection in a human in need thereof whichmethod comprises administering to said human a dosage of atherapeutically effective amount of amoxycillin in the range of 1400 to1900 mg, at dosage regimen interval of about 12 h, such that the dosageregimen provides a mean plasma concentration of amoxycillin of 4 1μg/mLfor at least 4.4 h, and a mean maximum plasma concentration (Cmax) ofamoxycillin of at least 12 μg/mL.
 12. The method according to claim 11in which the dosage regimen provides a mean plasma concentration ofamoxycillin of 4 μg/ml for at least 4.8 h and a mean maximum plasmaconcentration (Cmax) of amoxycillin of at least 16 μg/ml.
 13. The methodaccording to claim 11 in which the dosage is delivered from a modifiedrelease formulation.
 14. The method according to claim 11 in which thedosage is 1500 or 1750 mg of amoxycillin.
 15. The method according toclaim 11 in which the infection is caused by the organisms S pneumoniae(including Drug Resistant and Penicillin Resistant S pneumoniae), Hinfluenzae, M catarrhalis and/or S pyogenes.